WO2007102571A1 - Agent thérapeutique contre une maladie fonctionnelle du cerveau - Google Patents

Agent thérapeutique contre une maladie fonctionnelle du cerveau Download PDF

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Publication number
WO2007102571A1
WO2007102571A1 PCT/JP2007/054512 JP2007054512W WO2007102571A1 WO 2007102571 A1 WO2007102571 A1 WO 2007102571A1 JP 2007054512 W JP2007054512 W JP 2007054512W WO 2007102571 A1 WO2007102571 A1 WO 2007102571A1
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WO
WIPO (PCT)
Prior art keywords
disorder
salt
propyloctanoic acid
hydrochloride
agent
Prior art date
Application number
PCT/JP2007/054512
Other languages
English (en)
Japanese (ja)
Inventor
Rika Shinagawa
Yoshifumi Kagamiishi
Taiji Shimoda
Original Assignee
Ono Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ono Pharmaceutical Co., Ltd. filed Critical Ono Pharmaceutical Co., Ltd.
Priority to US12/282,298 priority Critical patent/US9517221B2/en
Priority to ES07738003T priority patent/ES2384034T3/es
Priority to EP07738003A priority patent/EP1997486B1/fr
Priority to JP2008503903A priority patent/JP5195418B2/ja
Publication of WO2007102571A1 publication Critical patent/WO2007102571A1/fr
Priority to US15/342,046 priority patent/US20170049737A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to a preventive, therapeutic and Z or symptom progression inhibitor for functional brain diseases comprising (2R) -2-propyloctanoic acid or a salt thereof.
  • brain diseases are roughly classified into organic brain diseases and functional brain diseases depending on whether or not a lesion is recognized in the cranial nerve tissue.
  • functional brain diseases in which no organic changes (lesions) are observed in the cranial nerve tissue are considered to be caused by some kind of brain dysfunction, brain neurotransmitter imbalance, or environmental factors or genetic predispositions. It has been.
  • depression and anxiety disorders which are typical functional brain diseases
  • various drugs for the treatment are being developed.
  • the treatment of depression includes tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase (MAO) inhibitors, serotonin and noradrenaline reuptake inhibitors (SNRI), selective serotonin reactivation.
  • Uptake inhibitors (SS RI) are used.
  • these drugs have inadequate therapeutic effects, take a long time to appear, or have side effects such as drowsiness, dry mouth, constipation, and difficulty in urinating. There are some problems that need to be improved.
  • benzodiazepines In the treatment of anxiety disorders, benzodiazepines, chenodiazepines, and non-benzodiazepines are used. However, these drugs have sufficient therapeutic effect, or have psychomotor functions, reduced concentration and attention, side effects such as drowsiness, lightheadedness, illusion, headache, and amnesia Problems such as these are recognized.
  • (2R) -2-propyloctanoic acid has also been reported to be useful as a nerve regeneration promoter in the treatment and Z or prevention of various neurodegenerative diseases (for example, International Publication No. 2005Z032535 pamphlet (see Patent Document 3).
  • Patent Document 1 European Patent No. 0632008
  • Patent Document 2 European Patent Publication No. 1174131
  • Patent Document 3 International Publication No. 2005Z032535 Pamphlet
  • An object of the present invention is to provide a safe drug having an excellent therapeutic effect on functional brain diseases represented by depression, anxiety disorder and the like.
  • the present invention provides: [1] (2R) 2-propyloctanoic acid or a salt thereof, a preventive or therapeutic agent for functional brain disease and a Z or symptom progression inhibitor; [2] The agent according to the above-mentioned [1], comprising about 5000 mg of (2R) -2 propyloctanoic acid or a salt thereof; [3] the functional brain disease is mood disorder and Z or anxiety disorder [1] [4] Functional brain disease is depression, menopausal mood disorder, perimenopausal mood disorder, panic disorder, irritable bowel syndrome, social anxiety disorder and Z or post traumatic stress disorder [5] The agent according to the above [3]; Schizophrenia drug, antiepileptic drug, anti-seizure drug, asthma drug, peptic ulcer drug, gastrointestinal function regulator, gastrointestinal motility drug, anti-diarrheal drug, antiphlogistic drug, antihypertensive drug , An antiarrhythmic drug, a cardio
  • (2R) -2-propyloctanoic acid is represented by the formula (I)
  • [0016] represents a ⁇ -configuration. It is a compound shown by this.
  • the salt of (2R) -2-propyloctanoic acid is preferably a pharmaceutically acceptable salt.
  • the pharmaceutically acceptable salt is preferably non-toxic and water-soluble.
  • suitable salts of (2R) 1-2-propyloctanoic acid include salts with inorganic bases, salts with organic bases, and salts with basic natural amino acids.
  • Examples of the salt with an inorganic base include alkali metal salts (for example, sodium salt, potassium salt, lithium salt, etc.), ammonium salts (for example, tetramethyl ammonium salt, tetraptyl ammonium salt). Etc.) is preferred.
  • salts with organic bases include alkylamines (eg, methylamine, dimethylamine, trimethylamine, triethylamine, etc.), heterocyclic amines (eg, pyridine, picolin, piperidine, etc.), alkanolamines (eg, For example, ethanolamine, diethanolamine, triethanolamine, etc.), dicyclohexylamine, ⁇ , ⁇ , monodibenzylethylenediamine, cyclopentylamine, benzylamine, dibenzylamine, phenethylamine, tri
  • alkylamines eg, methylamine, dimethylamine, trimethylamine, triethylamine, etc.
  • heterocyclic amines eg, pyridine, picolin, piperidine, etc.
  • alkanolamines eg, For example, ethanolamine, diethanolamine, triethanolamine, etc.
  • dicyclohexylamine ⁇ , ⁇ , monodibenzylethylened
  • the salt with a basic natural amino acid is not particularly limited as long as it is a salt with a basic amino acid that exists in nature and can be purified.
  • a salt with arginine, lysine, ornithine, histidine and the like Is preferred.
  • (2R) 2 Propyloctanoic acid or a salt thereof can be obtained by a method known per se, for example, European Patent No. 0632008, International Publication No. 99/58513, International Publication No. 00/4 8982.
  • the product of the reaction can be purified by conventional purification means such as distillation under normal or reduced pressure, high-speed liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, or column chromatography or washing, recrystallization. It can refine
  • the (2R) 2 propyloctanoic acid or a salt thereof used in the present invention is not limited to a substantially pure and single substance, but includes impurities (for example, by-products derived from the production process). , Solvents, raw materials, etc., or degradation products, etc.) may be contained as long as they are acceptable as an active pharmaceutical ingredient.
  • impurities for example, by-products derived from the production process.
  • the content of impurities acceptable as an active pharmaceutical ingredient varies depending on whether (2R) -2-propyloctanoic acid or its salt is used, and also varies depending on the impurities contained.
  • (2R) -2-propyloctanoic acid used in the present invention in particular, (2R) -2-propyloctanoic acid having an optical purity exceeding about 99% ee, especially having an optical purity of about 99.3% ee or more ( 2R) -2-propyloctanoic acid is preferred.
  • the present invention provides an effective amount of (2R) -2-propyloctanoic acid or a salt thereof to mammals (eg, humans, non-human animals (eg, monkeys, hidges, sushi, horses, inu, Cats, rabbits, rats, mice, etc.), preferably humans (patients) to prevent and treat functional brain diseases and to suppress Z or symptom progression (hereinafter abbreviated as the method of the present invention). And a functional brain disease prevention and treatment and Z or symptom progression inhibitor (hereinafter sometimes abbreviated as the agent of the present invention) used in the method.
  • mammals eg, humans, non-human animals (eg, monkeys, hidges, sushi, horses, inu, Cats, rabbits, rats, mice, etc.)
  • a functional brain disease prevention and treatment and Z or symptom progression inhibitor hereinafter sometimes abbreviated as the agent of the present invention used in the method.
  • prevention means that functional brain disease does not occur, or that mild symptoms are caused even if it occurs, and “treatment” means that functional brain disease is alleviated.
  • Symptom progression inhibition means to suppress the increase in symptoms of functional brain disease.
  • prevention includes the meaning of suppressing the occurrence of the next seizure, for example, in a functional brain disease in which seizures occur periodically or irregularly.
  • a functional brain disease is any disease as long as it is a disease in which nerve degeneration or the like is not recognized in the cranial nerve tissue.
  • body expression disorder for example, somatization disorder, conversion disorder, psychosis, pain disorder, body dysmorphic disorder, body expression autonomic dysfunction, persistent body expression pain disorder Etc.
  • anxiety disorders eg, panic attacks, panic disorder (interstitial seizure anxiety), phobias (phobic anxiety disorders) (eg height phobia, claustrophobia, acrophobia, agoraphobia Social phobia (social anxiety disorder), specific (individual) phobia, etc.
  • obsessive-compulsive disorder e.g.
  • Stress-related disorders e.g. post-traumatic stress disorder (PTSD), acute stress disorder, stress Inducible immune suppression, stress-induced headache, stress-induced fever, stress-induced pain, surgical attack stress, stress-related gastrointestinal dysfunction, irritable bowel syndrome, etc.
  • adjustment disorders e.g.
  • dissociative disorder eg dissociative amnesia, dissociative stagger (fugue), dissociative stupor, trans and dependent disorder, dissociative movement disorder, dissociative spasticity, Dissociative numbness and sensory loss, mixed dissociative disorder, dissociative homogeneity disorder, divorce disorder, etc.
  • mood disorders eg, depression (eg, major depression, mild depression, moderate depression) Disease, severe depression without psychotic symptoms, severe depression with psychotic symptoms or episodes thereof, single episode depression, recurrent depression, postpartum depression, child abuse-induced depression, senile depression , Masked depression, seasonal depression etc.), gonorrhea (eg hypomania, gonorrhea without psychotic symptoms, gonorrhea with psychotic symptoms or their episodes), bipolar disorder (eg hypomania
  • Recurrent depressive disorder eg mild episodes, moderate episodes, severe episodes without psychotic symptoms, severe episodes with psychotic symptoms, those in remission
  • dysthymic disorder mood circulation Sexual disabilities, solitary affective disorders, recurrent emotional disorders, indefinite complaints, premenstrual dysphoric mood disorders, postpartum mood disorders, perimenopausal mood disorders, menopausal mood disorders, etc.
  • suicide self-injury, personality disorder [eg Delusional personality disorder, schizophrenic personality disorder, non-social personality disorder, emotional instability personality disorder, impulsive personality disorder, borderline personality disorder, other emotional anxiety Personality disorder, acting personality disorder, obsessive-compulsive personality disorder, anxiety (avoidance) personality disorder, dependent personality disorder, persistent personality change, pathological gambling, pathological arson (arson), pathological theft (theft) ), Hair loss etc.], mental sexual disorders [eg, sexual dysfunction (eg, decreased sexual desire disorder, sexual aversion disorder, sexual dysfunction due to physical disorder, substance-induced sexual dysfunction,
  • the route of administration may be oral administration or parenteral administration.
  • Parenteral administration may be systemic administration such as intravenous administration, or local administration such as intrathecal administration and transdermal administration.
  • the dose of (2R) -2-propyloctanoic acid or its salt is the dose that is effective against the above-mentioned diseases where (2R) -2-propyloctanoic acid or its salt does not show significant toxicity in vivo. Any dose can be used, but it is usually used in the range of about 1 mg to about 5000 mg.
  • the administration method is changed.
  • a suitable dose may be selected according to the conditions.
  • As a guideline for the dose of (2R) -2-propyloctanoic acid or a salt thereof for example, when orally administering (2R) -2-propyloctanoic acid or a salt thereof, (2R) -2-propyloctanoic acid or The dose per salt is particularly preferably about 300 mg to about 1500 mg, preferably about 50 mg to about 5000 mg, more preferably about 100 mg to about 2000 mg.
  • the dose per dose of (2R) -2-propyloctanoic acid or a salt thereof is preferably about 50 mg to about 2000 mg. Particularly preferred is about 150 mg to about 1200 mg, with about 10 mg to about 1500 mg being more preferred.
  • the dose per dose of (2R) 2-propyloctanoic acid or a salt thereof is about lmg to about Particularly preferred is about lOmg to about 500 mg, where lOOOmg is preferred, and about lmg to about 500 mg is more preferred.
  • (2R)-2 propyloctanoic acid or a salt thereof when administered transdermally, (2R) -2-propyloctanoic acid or The preferred dose per salt is about 1 mg to about 50 mg, preferably about 1 mg to about 500 mg.
  • the dosage shown above is preferred as the amount of (2R) 2-propyloctanoic acid.
  • the dose is preferably used in order to obtain the preferred prevention, treatment and Z or symptom progression inhibitory effects on the functional brain disease.
  • mammals eg, humans, non-human animals, etc., preferably humans (patients)
  • it is more preferable to administer it for example, about 2 mg to about 18 mg, such as about 1 mg to about 20 mg, etc.
  • More specific doses include, for example, about 2 mg, about 4 mg, about 6 mg, about 8 mg, about 10 mg, about 12 mg, about 15 mg, or about 18 mg per kg body weight of the patient.
  • the amount includes, for example, about 4 mg, about 6 mg, about 8 mg, about 10 mg or about 12 mg per 1 kg body weight of the patient.
  • the most preferable dosage includes, for example, about 8 mg or about 10 mg per lb g body weight of the patient.
  • (2R) -2 propyloctanoic acid or a salt thereof when administered intravenously, it may be rapidly injected by one shot! /, And intravenously using a syringe or an infusion bag. May be administered continuously (preferably by intravenous infusion).
  • the time spent for the administration is not particularly limited, and may be changed depending on the condition of the mammal (for example, human non-human animal, preferably human (patient)) and other reasons. For example, from about 0.5 hours (about 30 minutes) to about 3 hours (about 180 minutes), preferably from about 0.5 (about 30 minutes) time to about 1.5 hours (about 90 minutes), Particularly preferred is about 1 hour (about 60 minutes).
  • compositions used for administration by injection are (2R) -2-propyloctanoic acid or its And metal salts commonly used in injections (for example, trisodium phosphate, disodium monohydrogen phosphate, sodium carbonate, sodium sulfite) and pH regulators (for example, sodium hydroxide, etc.) ), Stabilizers, surfactants, buffers, solubilizers, antioxidants, antifoaming agents, tonicity agents, emulsifiers, suspending agents, preservatives, soothing agents, solubilizers, solubilizers
  • additives such as those described in Yakuho Nippo 2000 “Pharmaceutical Additives Encyclopedia” (edited by the Japan Pharmaceutical Additives Association) etc.
  • solvents eg, distilled water for injection.
  • solvents eg, distilled water for injection.
  • electrolytes eg, sodium chloride, sodium chloride, potassium salt, calcium carbonate, sodium lactate, sodium dihydrogen phosphate, sodium carbonate, magnesium carbonate, etc.
  • Sugars eg, glucose, fructose, sorbitol, mannitol, dextran, etc.
  • protein amino acids eg, glycine, aspartate, lysine, etc.
  • vitamins eg, vitamin Bl, vitamin C, etc.
  • Ingredients generally used for infusion can also be used.
  • Such a pharmaceutical composition is sterilized in the final step or manufactured and prepared by an aseptic operation.
  • a sterile solid preparation such as a freeze-dried product can be produced and used by dissolving in sterilized or sterile purified water or other solvent before use.
  • a pharmaceutical composition used for oral administration may be a dosage form that can be administered orally to mammals (eg, humans, non-human animals, etc., preferably humans (patients)). Anything may be used.
  • a preparation for oral administration containing (2R) -2-propyloctanoic acid or a salt thereof used in the present invention for example, tablets, force capsules, fine granules, granules, powders, etc. are preferred. Particularly preferred are capsules, especially soft capsules.
  • preparations such as tablets, fine granules, granules, powders, etc.
  • (2R)-2-propyloctanoic acid or a salt thereof are prepared from (2R) -2-propyloctanoic acid or a salt thereof and commonly used excipients (for example, sucrose, lactose, glucose, Starch, mannitol, sorbit, cellulose, talc, cyclodextrin, etc.), binder (eg, cellulose, methylcellulose, polybulurpyrrolidone, gelatin, gum arabic, polyethylene glycol, sucrose, starch, etc.), disintegrant (eg, denpun) , Carboxymethylcellulose, calcium salts of carboxymethylcellulose, etc.), lubricants (for example, talc, etc.) and the like.
  • excipients for example, sucrose, lactose, glucose, Starch, mannitol, sorbit, cellulose, talc, cyclodextrin, etc.
  • binder eg, cellulose, methylcellulose, polybulurpyrroli
  • a soft capsule agent is (2R) -2-propyloctanoic acid or a salt thereof, which is commonly used as a turnip. It can be manufactured by coating with a cell coating.
  • Capsule coatings are capsule bases [eg, proteins (eg, gelatin, collagen, etc.), polysaccharides (eg, starch, amylose, polygalataturonic acid, agar, carrageenan, gum arabic, dielan gum, xanthan gum, pectin, alginic acid, etc.)
  • Biodegradable plastics eg, polylactic acid, polyhydroxybutyric acid, polyglutamic acid, etc.
  • hardened fats and oils eg, triglycerides or diglycerides of medium chain fatty acids
  • plasticizers eg, sugars (eg, sucrose, sucrose) ), Sugar alcohol (eg, sorbitol, xylitol, mannitol, etc.), polyhydric alcohol (
  • compositions used for transdermal administration should be in a dosage form that can be transdermally administered to mammals (eg, humans, non-human animals, etc., preferably humans (patients)). Anything may be used.
  • mammals eg, humans, non-human animals, etc., preferably humans (patients)
  • examples of the preparation for transdermal administration used in the present invention include liquid sprays, lotions, ointments, creams, gels, sols, aerosols, haps, plasters, tapes and the like.
  • These compositions include (2R) -2-propyloctanoic acid or a salt thereof and an oily base generally used for external preparations (eg, vegetable oil (eg, cottonseed oil, sesame oil, olive oil, etc.), wax (E.g.
  • Cellulose derivative solution or polymer hydrated gel polyethylene glycol (Pharmacopoeia macrogol), polyethylene glycol polypropylene glycol copolymer, propylene glycol, 1, 3 butylene glycol, ethanol, glycerin etc.], tape agent Adhesives used [for example, synthetic rubber-based adhesives (for example, methacrylic acid ester copolymers, natural rubber-based adhesives, synthetic isoprene, etc.), silicone polymer-based adhesives, etc.] film bases [for example, polyethylene , Polypropylene, polyethylene, butyl acetate copolymer, PET, aluminum laminate, etc.], gel base [eg, dry agar, gelatin, aluminum hydroxide, caustic acid, etc.], or oil base and water soluble base Agents [eg, anionic surfactants (eg, fatty acids, saponins, fats Sarcoside, alcohol sulfate ester, alcohol phosphate ester, etc.), cationic surfact
  • surfactants eg anionic surfactants (for example, fatty acids, saponins, fatty acid sarcosides, alcohol sulfates, alcohol phosphates, etc.), positive Ionic surfactants (eg, quaternary ammonium salts, heterocyclic amines, etc.), amphoteric surfactants (eg, alkylbetaines, lysolecithins, etc.), nonionic surfactants (eg, polyoxyethylene alkyl esters) Tereline, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, etc.]], thickener [eg, cellulose derivatives (eg, carboxymethyl cellulose), polycarboxylic acids (eg, polyacrylic acid, methoxymethylene maleic anhydride) Copolymers), nonionic water-soluble polymers (eg, polyvinylpyrrolidone, polyvinyl chloride) Etc.], stabilizedionic surfactants [eg,
  • Liquid sprays, lotions, sols or aerosols can be prepared using (2R) -2-propyloctanoic acid or its salt in a solvent such as water, propylene glycol, 1,3-butylene glycol, ethanol or glycerin. In addition, it can be produced by dissolving or dispersing. Moreover, the said additive can also be customized if desired.
  • (2R) -2-propyloctanoic acid or a salt thereof is usually used in the technical field such as the water-soluble base, the oil-based base and Z or water, vegetable oil or the like. It can be produced by mixing with a solvent, adding a surfactant as necessary, and emulsifying. Moreover, the said additive can also be customized if desired.
  • the haptic agent, plaster agent, or tape agent is a solution containing (2R) -2-propyloctanoic acid or a salt thereof and the pressure-sensitive adhesive (which may contain the additive if necessary). ! ⁇ ) can be applied to the film base and subjected to crosslinking treatment or drying operation as necessary.
  • the gel is prepared by pouring a solution containing (2R) -2-propyloctanoic acid or a salt thereof and the gel base (which may contain the additive if necessary) into a mold. If necessary, it can be produced by performing a crosslinking treatment or a drying operation.
  • the dosage period of the pharmaceutical composition is, for example, as long as a prophylactic effect is expected. Until the onset of functional brain disease is substantially suppressed, for example, if a therapeutic effect is expected, until the treatment is substantially completed, for example, if a symptom progression suppressing effect is expected, symptom progression Any period of time until substantially suppressing is possible. If desired, it may be administered intermittently with an appropriate drug holiday. For intermittent administration, it is preferable that the withdrawal period is 1 day or more and 30 days or less.
  • intermittent administration during a day off, or a calendar system e.g. Called.
  • administration is generally performed 2 to 3 times a week.
  • a specific dosing period in the agent of the present invention for example, for oral administration or transdermal administration, 1 day to 5 years, etc., preferably 1 day to 1 year, etc., more preferably One day to six months, etc., particularly preferably one day to two months, etc. are mentioned.
  • 1 day to 100 days, etc. preferably 1 day to 10 days, etc., more preferably 1 day to 7 days, etc., most preferably 7 days, etc.
  • intrathecal administration 1 day to 3 years, etc., preferably 1 day to 1 year, etc., more preferably 1 day to 6 months, etc., most preferably 1 day to 3 months, etc. Is mentioned.
  • the number of doses per day during these dosing periods is, for example, 1 to 5 times, preferably 1 to 3 times, etc. in the oral administration and intravenous administration forms. Preferred is once or twice, most preferably once.
  • intrathecal administration it may be administered once or twice a day, but intermittent administration is preferred as described above.
  • transdermal administration can be expected to have an effect of controlling the blood concentration, and can be interrupted when an adverse event commonly referred to as a side effect occurs.
  • composition comprising (2R) -2-propyloctanoic acid or a salt thereof used in the present invention may be used alone, or may be used for the treatment of functional brain disease. It can also be used in combination with other drugs and treatment methods (eg, counseling).
  • a pharmaceutical composition containing (2R) 2 propyloctanoic acid or a salt thereof is used in combination with another drug, it is administered in the form of a combination drug containing both components in one preparation. It may also take the form of administration as a separate formulation. Administration as separate formulations includes simultaneous administration and administration by time lag.
  • anxiolytic drugs e.g., benzodiazepine anxiolytics, chenodiazepine anxiolytics, non-benzodiazepine anxiolytics, serotonergic drugs, CRF antagonists, tachycun N K1 antagonists, MBR ligands, etc.
  • antidepressants eg, tricyclic antidepressants, tetracyclic antidepressants, monoamine liberators, monoamine oxidase (MAO) inhibitors, monoamine reuptake inhibitors ( SSRI, SNRI), CRF antagonist, Takikun NK1 antagonist, neurotensin antagonist Drugs, psychostimulants, anxiolytics, antipsychotics, etc.
  • antiparkinsonian drugs e.g., anticholinergics, dopamine receptor agonists, monoamine oxidase (MAO) inhibitors
  • schizophrenia treatments e.g., schizophrenia treatments (E.g.
  • dopamine receptor antagonists dopamine receptor antagonists
  • antiepileptic drugs e.g. barbiturate antiepileptics, hydantoin antiepileptics, etc.
  • antispasmodics asthma drugs (e.g. bronchodilators, alpha receptors) Physical agonists, 2-receptor agonists, xanthine derivatives, inhaled steroids, anticholinergic agents, 5-lipoxygenase inhibitors, etc.), peptic ulcer drugs (for example, aggressive factor inhibitors, anti-pepsin drugs, anticancer drugs) Acid drugs, histamine ⁇ 2 receptor antagonists, anti-gastrin drugs, proton pump inhibitors, muscarinic receptor antagonists, anticholinergics, defense factor potentiators, prostaglandin derivatives, etc.) diarrhea ⁇ receptor stimulants, etc.), laxatives (eg, expansive laxatives, salt laxatives, stimulant laxatives, affinity polyacrylic resins, etc.
  • dysuria drugs for example, frequent urination drugs, anticholinergic drugs, muscarinic receptor agonists (antagonists) drugs, tachycun NK1 antagonists, ⁇ 2 antagonists, etc.
  • digestive organs Functional modulators and sputum or gastrointestinal motility-promoting drugs e.g., intestinal regulating agents, CCK-A antagonists, new mouth tensin antagonists, opioid receptor agonists, muscarinic receptor agonists, 5--4 agonists
  • Drugs e.g., 5- (3) antagonists, etc.
  • examples of the 5- ⁇ 3 antagonist include (alosetron (hydrochl oride)) and the like.
  • 5-HT4 agonist examples include (tegaserod (maleate)), cisapride [Cisapride], mosapride citrate (mosapride citrate), and the like.
  • Examples of the a 1 receptor blocker include AIO-8507L, indolamine, urapidil, silodosin, naphthovir, doxazosin mesylate, alfuzosin hydrochloride, tamsulosin hydrochloride, terazosin hydrochloride, bunazosin hydrochloride, prazosin hydrochloride, and the like. .
  • Examples of a receptor agonist include mitodrine hydrochloride and the like.
  • ⁇ 2 receptor agonists include, for example, AR-C68397, AR—C89855, KUL—72 11, KUR-1246, R, R-formoterol, S-1319, Epinephrine, Xinafoic acid Sanoremetellonore, Rolbuteronore, Bambuteronore, Fuonoremoterenole, Fumanoleic acid formoterol, Levosalbutamol, Clenbuterol hydrochloride, dipivefrin hydrochloride , Lobbuterol hydrochloride, dopexamine hydrochloride, trimetoquinol hydrochloride, pyrbuterol hydrochloride, pro-powered terol hydrochloride, mabuterol hydrochloride, ritodrine hydrochloride, meladrin tartrate, fenoterol hydrobromide, isoproterenol sulfate, orciprenaline sulfate, chlorpre
  • ⁇ receptor blockers include, for example, timolol maleate, benolol hydrochloride hydrochloride, cartelolol hydrochloride, betaxolol hydrochloride, atenolol, nadolol, dipradilol, pindolol, bisoprolol fumarate, popindrol malonate, acebutolol hydrochloride, hydrochloric acid Examples include alprenolol, indenolol hydrochloride, oxprenolol hydrochloride, seriprolol hydrochloride, tilisolol hydrochloride, bucmolol hydrochloride, bufetrol, hydrochloride bupranolol, propranolol hydrochloride, betaxolol hydrochloride, metoprolol tartrate, and penbutolol sulfate.
  • angiotensin II receptor antagonist for example, oral sultan (potassium) [losartan
  • angiotensin converting enzyme inhibitors include alacepril [alacepril], tapril hydrochloride [imidapril hydrochloride], quinapril hydrochloride [quinapril hydrochloride], temocapril hydrochloride hydrochloride [temocapril hydrochloride], telapril hydrochloride hydrochloride [delapril hydrochloride], hydrochloric acid Examples include benazepril hydrochloride, captoprinol [captopril], trandolaprinol [trandolapril], perindopril erbumine, enalapril maleate, and lisinopril.
  • opioid receptor agonists include opium Alkaloids and Atropine, opium alkaloids and opium, opium alkaloids hydrochloride, opium alkaloids hydrochloride, opium alkaloids hydrochlorides, opium alkaloids and Atropine.
  • Calcium antagonists include, for example, difedipine [Nifedipine], bedidipine hydrochloridej, dinortiazem hydrochloridej, verapamil hydrochloride, nisoldipinej, nitorenpine [nitrendipine] , Bepridil hydrochloride, amlodipine besinoleate, lomerizine hydrochloride, efonidipine hydrochloride, and the like.
  • xanthine derivatives include aminophylline, theophylline, doxophylline, cypamphylline, diprophylline, and the like.
  • serotonergic agents include sumatributane [Sumatriptan], sumatriptan succinate [Sumatriptan succinate], zonoremitriptan [Naratrip tan], rizatriptan [Rizatriptan], benzoic acid Rizatriptan [Rizatriptan benzoate], eletriptan [Eletriptan], eletriptan hydrobromide [Eletriptan hydrobromide], almotriptan [Almotriptan], frovatriptan [Frovatriptan] and the like.
  • Examples of chenodiazepine anxiolytics include ethizolam [Etizolam] and clothiazepam [Clotiazepam].
  • Dopamine receptor agonists include, for example, L-dopa [L-dopa], amantadine [Am antadine, cabergoline, talipexole, pergolide, pramipexole, bromocriptine, and so on.
  • Sodium channel antagonists include, for example, ajmaline [Ajmaline], aprindine hydrochloride [Amiodarone hydrochloride], nsopyramide [Disopyramide], disopyramide phosphate [Disopyramide Phosphate], pilsicaide hydrochloride [ Pilsicainide hydrochloride, Pirmenol Hydrochloride, Procainamide hydrochloride, Propafenone hyd rochloride, Flecainide Acetate, Mexiletine hy drochloride, Lidocaine hydrochloride Hydrochloride], lidocaine [Lidocaine] and the like.
  • Antiepileptic drugs include, for example, Acetazolamide [Acetazolamide], Acetylpheneturide [Ethosuximide], Ethotoin [Ethotoin], Canolenomazepine [Carbamazepine], Clonazepam [Clonazepam] [Clobazam] ⁇ Diazepam [Diazepam], Sultiame [Zultsamide], Trimethadione [Trimethadione] ⁇ Nitrazepam [Nitrazepam], Vanoleproic acid [Valproate], Sodium valoreproate [Sodium valproate], Fetoin Phenytoin], phenobarbital [Phenob arbital], phenobarbital sodium [Phenobarbital sodium], primidone [Primidone], metalbital [Metharbital], mehobarbital [Mephobarbital], carbonic anhydrase inhibitors and the like.
  • histamine H2 receptor antagonists include famotidine, latidine, and cimetidine.
  • Examples of the prostaglandin derivative include ornoprostil [Ornoprostil], misoprostol [Misoprostol], and enprostil [Enprostil].
  • proton pump inhibitors examples include omebrazole [Omeprazole], lansoprazo monol [Lansoprazole], rabeprazole sodium [Rabeprazole sodium] and the like.
  • Examples of benzodiazepine anxiolytics include Alprazolam, Sazepam [Oxazepam], Oxazolam [Oxazolam], Cloxazolam [Cloxazolam], Dipotassium chlorazepate [Clorazepate dipotassium], Chronodiazepoxide [Chlordiazepoxi de], Diazepam [Diazepam], Tofisopam [Tofisopam], Triazolam Prazepam, Fludiazepam, Flutazolam, Furtov.
  • Examples include lazenom [Flutoprazepam], bromathenomu [Bromazepam], mexazobum [Mexazolam], medazepam [Medazepam], loflazepate ethinore [Ethyl loflazepate], and lorazepam [L orazepam].
  • Phosphodiesterase inhibitors include, for example, Siromilast (trade name: Ariflo) (Pre-reg; 200408, IDdb3), Mouth Flumilast (BY—217) (Pr e-reg 200408, IDdb3), Arofylline (PHI; 200408, IDdb3), OPC—653 5 ( ⁇ ; 200408, IDdb3), ONO— 6126 (PII; 200408, IDdb3), IC—485 (PII; 20040 8, IDdb3), AWD—12—281 ( ⁇ ; 200408, IDdb3), CC—10004 (PII; 200408, IDd b3), CC-1088 (PII; 200408, IDdb3), KW—4490 ( ⁇ ; 200408, IDdb3), Lirimil ast (PII; 200408, IDdb3), ZK—117137 ( ⁇ ; 200408, IDdb3), YM—976 (PI; 200 408, IDd
  • muscarinic receptor antagonists examples include pirenzepine and the like.
  • Examples of the monoamine oxidase (MAO) inhibitor include safrazin hydrochloride, selegiline hydrochloride, deprnyl, riluzole, and remacemide.
  • Monoamine reuptake inhibitors include, for example, (Tra zodone (Hydrochloride)), (Moleic acid) Funoleboxamine [Fluvoxamine (Maleate), ( Hydrochloric acid) Milnacipran (Hydrochloride)] and the like.
  • salt laxatives include magnesium sulfate and magnesium oxide.
  • Inhaled steroids include, for example, beclometasone dipr opionate, fluticasone propionate, budeson ide, fludeoride, triamcinolone, and triamcinolone.
  • -Cicles onide Dexamethasone Paromithionate [Dexamethasone], Mometasone Francobone ⁇ Motosone!
  • Examples include streptanate [Methylprednisolone sule ptanate], methinoreprednisolone sodium succinate, and ST-126P.
  • anti-gastrin drug examples include proglumide [Proglumide], oxesasein [Oxeth azaine] and the like.
  • anticholinergic agent examples include trihexyphenidyl, trihexyphenidyl hydrochloride, biperiden, biperiden hydrochloride, and the like.
  • anti-pepsin drug examples include sucralfate [Sucralfate] and the like.
  • Antipsychotics include, for example, clofetaton [Clo Stammon], spiperone [Spiperone], sulpiride [Sulpiride], zotepine [Zotepine], timiperone [Halopendoi decanoate], acan Acid Fluphenazine [Fluphenazine decanoate], Noperoperidonore [Haloperidol], Pimozide [Propericiazine], Bromperidol [Bromperidol], Penolephenazine [Perphenazine], Lefopropromale maleate maleate maleate Examples include Roman [Chlorpromazine hydrochloride], thioridazine hydrochloride [Traz odone hydrochloride], mosafamine hydrochloride [Mosapramine hydrochloridej, serotonin and domino amine antagonists].
  • Anti-anxiety drugs include, for example, ⁇ -oryzanol [ ⁇ -oryzanol], alprazolam [Alpra zolam], etizolam [Etizolam], oxazepam [Oxazepam], oxazolam [Oxazolam], tandospirone citrate [Tandospirone citrate], cloxazolam [Cloxazolam], black Azepam [Clotiazepam], dipotassium chlorazepate [Clorazepate dipotassium], Chlorodiazepoxide [Chlordiazepoxide], diazepam [Diazepam], tofisopam [Tofisopam], triazolam [Triazolam], hydroxyzine hydrozine hydrochloride ], Prazenomu [Prazepam] ⁇ Funoreziazenomu [Fludi azepam], Funoretazolam
  • Examples of the antidepressant include diphenhydramine salicylate, diphenidol, difenidol, difenidol hydrochloride, betahistine, betahistine mesilate, and perphenazine.
  • Examples include [Perphenazine], penolephenazine hydrochloride [Perphenazine Hydrochloride], chloropromazine hydrochloride [Chlorpromazine Hydrochloride], sodium bicarbonate solution [Sodium Bicarbonate], and the like.
  • Examples of the tricyclic antidepressant include amitriptyline hydrochloride, amitriptyline, imipramine hydrochloride, imipramine, and kupukumifu hydrochloride.
  • Examples include [amoxapine], acid amph [desipramine hydrochloride], and desipramine.
  • Examples of the stimulant laxative include picosulfate, lactulose, castor oil, senna, and yellow.
  • tetracyclic antidepressants examples include mianserin hydrochloride, mianserin, maprotiline hydrochloride, maprotiline, setiptiline maleate maleate, and the like.
  • antacids for example, aluminum silicate [Aluminum Silicate], dry aluminum hydroxide gel [Dried Aluminum Hydroxide Gel], magnesium oxide [Magnesium oxide] ], Sodium hydrogen carbonate, sodium carbonate, [Calcium Carbonate] and the like.
  • Examples of the psychostimulant include methyl-fedate hydrochloride [Methylphenidate hydrochlo ride], pemoline [Pemoline] and the like.
  • non-benzodiazepine anxiolytics examples include tandospi rone citrate, hydroxyzine hydrochloride and the like.
  • Examples of the expansive laxative include methylcellulose, carmellose, and lactulose.
  • Examples of the protective factor enhancer include L-glutamine [L-Glutamine], sodium azulene sulfonate [Aceglutamide aluminum], sodium alginate [Sodium alginate] , Aldioxa, Ecabet sodium, Egualen sodium, Enprostil, Ornoprostil, Gefarna KGefarnate, Sucralfate, Sulpiride [Sulpiride], Sofalcone [Sofalcone], Teprenone [Te prenone], Troxipide [Troxipide], Plaunotol, Polaprezin [Polap rezinc], Inoresogladine maleate [Irsogladine maleate], Missov.
  • (2R) -2-Propyloctanoic acid or a pharmaceutical composition containing a salt thereof is used in combination with the pharmaceutical agent described above, and is not limited thereto.
  • the administration method of these drugs to be used in combination is not particularly limited, and may be oral or parenteral. These drugs may be administered in combination of any two or more. These drugs include not only those that have been found so far, but also those that will be found in the future based on the mechanism described above.
  • Examples of pharmacological tests other than those described in the examples include the following methods. These methods thus, the effect of (2R) -2-propyloctanoic acid or a salt thereof on functional brain disease can be proved. In the following method, various test conditions are examined so that the pharmacological action of (2R) -2-propyloctanoic acid or its salt can be appropriately evaluated, and improvement that improves the accuracy and Z or sensitivity of the evaluation. Can also be added.
  • trial, trial ⁇ row 1 7k immersion stress + trial
  • the rats in the control group are not subjected to water stress.
  • the vehicle is administered orally to the vehicle treatment group, and various concentrations of the test drug are administered to the test drug treatment group.
  • Test Example 2 Anti-stress action confirmation test
  • the learning helplessness test is performed using a two-way shuttle box that is divided into two parts by a gate that can be opened and closed and that can move left and right.
  • Wistar male rats are used, and shock training is performed on the first day of the test.
  • Shock training is performed by placing a rat in the device with the gate closed and inaccessible and applying an electrical shock (10 seconds x 90 times, 2 seconds interval) through the floor grid.
  • the rats in the control group are left in the apparatus for the same time without applying electric shock. Escape test is performed 24 hours after shock training.
  • the 'escape' test consists of placing the rat in the device with the gate open and allowing escape, after 5 minutes of habituation, simultaneously giving light and sound stimulation (conditional stimulation) for 5 seconds, followed by electric shock (unconditional) Stimulation) is given for 10 seconds. If the patient continues to receive an electric shock without escaping, the evacuation failure is repeated 40 times (5 second intervals), and the behavior of the rat is analyzed with behavior analysis software (MED-PC Version 1.16).
  • the vehicle and the test drug are orally administered once a day for 6 days, and further orally one hour before shock training on the seventh day.
  • Test Example 4 Antidepressant in an olfactory bulbectomized rat
  • Wistar male rats are used for the experiment.
  • Pentobarbital sodium Fix the anesthetized rat head to a stereotaxic device, open the scalp, open holes in the left and right olfactory bulbs using a dental drill, and suck and remove the left and right olfactory bulbs with an aspirator. Suture.
  • the suction and removal of the olfactory bulb is not performed, but a hole is made in the left and right olfactory bulb, and then the scalp is sutured.
  • Rats after excision of the olfactory bulb are placed in stainless steel five-segment cages, each of which is divided in half by an acrylic plate, and kept alone for 2 weeks. After that, it is subjected to the following ⁇ 4 2> and 4 3> experiments.
  • the vehicle and study drug are orally administered once a day for 7 days. Evaluation should be performed in a quiet environment before grouping and on the 1st and 7th days of study drug administration. The degree of irritation shall be scored according to the evaluation criteria shown below before grouping, before administration of study drug 7 days, and 1 hour after administration of study drug 1 day and 7 days.
  • A Reaction to a stick placed at the tip of the nose (0: No response, 1: Interest in the subject, 2: Defensive or escape behavior to the subject, 3: Aggressive behavior such as staring, 4: Strong attack
  • B Reaction when blowing air 4 (0: No response, 1: Slight body movement, 2: Startle response, 3: Shows a startle response, but does not fly, 4: Jump up with a remarkable startle response);
  • C resistance to capture and handling (0: no resistance, significant muscle relaxation, 1: easy to capture and handle, 2: easy to capture and handle, but mild muscle tension, 3: with muscle tone, Difficult to handle, 4: extremely difficult to capture and significant muscle tension);
  • D Reaction when the tail is pinched with forceps (0: No response, 1: Interest in the subject, 2: Defensive or escape behavior to the subject, 3: Aggressive behavior such as sneaking, 4 : Severe aggressive behavior);
  • (2R) -2-propyloctanoic acid which is the test drug, suppresses the enhancement of hyperactivity seen in the vehicle-treated group. From this result, it can be proved that (2R) -2-propyloctanoic acid has an antidepressant action.
  • An elevated plus-maze device with a wallless open arm and a walled closed arm force is used for the test.
  • the equipment will be installed with a floor force of 60cm. Observe in a dimly lit room. Adjust the lighting so that the illuminance inside the closed arm is about half that on the open arm.
  • Anxiety behavior is analyzed by a video image behavior analysis device.
  • the vehicle and the test drug are orally administered once a day for 8 days.
  • the study was Apply. Two hours after dosing, place the animal gently in the center of the platform with one open arm and measure for 5 minutes. However, if the animal falls, it will be staying in the open arm, and immediately return the animal to the place or platform where it was just before the open arm fell.
  • the following items (1) to (6) are measured using a video image behavior analyzer, and (7) and (8) are measured after the measurement is completed.
  • (2R) 2-Propyloctanoic acid or a salt thereof is very low in toxicity and can be judged to be sufficiently safe for use as a medicine.
  • (2R) -2-propyloctanoic acid was found to be dead at lOOmgZkg.
  • the present invention aims to prevent and treat functional brain diseases and to suppress Z or symptom progression.
  • (2R) An effective amount of 2-propyloctanoic acid or a salt thereof is administered.
  • the pharmaceutical composition containing (2R) -2-propyloctanoic acid or a salt thereof used in the present invention contains (2R) -2-propyloctanoic acid or a salt thereof as an active ingredient, and is a mammal.
  • mammals for example, humans, non-human animals such as monkeys, hidges, ushi, Can be used for the above purpose in ma, inu, cats, rabbits, rats, mice, etc.).
  • the preferred usage 'dose exemplified in the present invention is that it is administered orally or parenterally to mammals (eg, humans, non-human animals, etc., preferably humans (patients)), and also into the medullary cavity.
  • mammals eg, humans, non-human animals, etc., preferably humans (patients)
  • medullary cavity e.g. depression, perimenopausal mood disorder, perimenopausal mood disorder, panic disorder, irritable bowel syndrome, social anxiety disorder, post-traumatic stress disorder, etc. It is possible to obtain favorable effects on functional brain diseases represented by
  • the present invention provides a specific method for using (2R) -2-propyloctanoic acid or a salt thereof for the prevention and treatment of functional brain disease and Z or suppression of symptom progression.
  • (2R) -2-propyloctanoic acid or a salt thereof for the prevention and treatment of functional brain disease and Z or suppression of symptom progression.
  • by administering (2R) -2-propyloctanoic acid or a salt thereof in the preferred usage and dosage exemplified in the present invention depression, menopausal mood disorder, perimenopausal mood disorder, panic disorder, irritable bowel It can prevent, treat, and suppress Z or symptom progression for functional brain diseases represented by syndrome, social anxiety disorder, and post-traumatic stress disorder.
  • a desirable effect on functional brain disease can be shown.
  • the group composition and drug administration method are as shown below.
  • each drug solution or vehicle was orally administered at a liquid volume of 5 mLZkg once a day for 8 days, for a total of 8 times.
  • Sham operation group vehicle (0. lvol% Tween80) aqueous solution
  • Vehicle control group vehicle (0. lvol% Tween 80) aqueous solution
  • (2R) 2-Propyloctanoic acid 3 mgZkg administration group: (2R) — 2-Propyloctanoic acid prepared in a medium to 0.6 mgZmL;
  • (2R) (2R) — Drug solution prepared with 2-propyloctanoic acid in a medium to 2. Omg / mL;
  • Milnacipran hydrochloride lOmgZkg administration group Chemical solution prepared with 2.3 mg / mL of milnacipran hydrochloride in a medium (including 2. Omg / mL as milnacipran).
  • Emotional hyperreactivity was evaluated by (1) before grouping, (2) 1 hour after administration of test drug 1 day to 1 hour 10 minutes, (3) 7 days before administration and (4) after administration 1 From 1 hour to 10 minutes (4 times in total), once per animal, the degree of irritability was evaluated according to the following emotional hyperresponsiveness evaluation criteria (excessive emotion score: Gomida et al. Method (Folia Pharmacologica Japonica, 82, 267 , 1983). All evaluations were recorded with a video camera (SSC-DC430, Sony Corporation) and used as reference data.
  • (2R) 2-Propyloctanoic acid suppressed the increase in hyperactivity seen in the vehicle control group of olfactory bulbectomized rats.
  • the results are shown in Table 1 below.
  • (2R) -2-Propyloctanoic acid suppressed the increase in hyperactivity seen in the vehicle control group on day 1 and day 7 of administration.
  • (2R) -2-propyloctanoic acid has been shown to be effective in both single and continuous administration, and has excellent prevention and treatment for mood disorders such as depression and Z. It was also found to have an effect of suppressing symptom progression.
  • Evaluation of anxiety behavior on the elevated plus maze was performed by analyzing each animal for 5 minutes, 1 hour to 1 hour and 10 minutes after administration of the test drug on the 8th day, according to the following method.
  • the animal was placed gently on the elevated plus-maze platform described below, facing one open arm. Then, the behavior of the animals was photographed with a video camera (CCD-DC430, Sony Corporation) installed on the elevated plus maze, and the video was analyzed with a video image behavior analyzer (Etho Vision, Noldus). In addition, the video from the video camera was recorded and treated as reference data. If the animal fell, it was assumed that it was staying on the open arm, and it was immediately returned to the place where it was just before the open arm fell.
  • the evaluation is based on the items indicated by AH (A: Number of times of entering the open arm, B: Number of times of entering the closed arm, C: Number of times of entering the platform, D: Time spent on the open arm (seconds), E: Time spent on the closed arm (seconds), F: Time spent on the platform (seconds), G: Number of feces on the open arm, platform, closed arm, H: The number of urinations on the open arm, platform and closed arm) was measured using a video image behavior analyzer for AF and G and H after measurement was completed.
  • the elevated cross maze was an open arm with no walls and a closed arm force with walls, and the bottom of the arm was painted black and the side was painted white.
  • the size of the elevated cross maze is 42 cm long and 15 cm wide for both open and closed arms.
  • the height of the wall of the closed arm is 30 cm and the device is installed 60 cm above the floor.
  • the room brightness was set so that the illuminance on the elevated plus maze was 430 Lux.
  • (2R) 2-propyloctanoic acid suppressed the anxiety behavior seen in the vehicle control group. Therefore, (2R) -2-propyloctanoic acid has been shown to have excellent preventive 'treatment and an inhibitory effect on Z or symptom progression against anxiety disorders.
  • Gelatin (20 kg) and concentrated glycerin (6 kg) were mixed at 70 ° C. in the presence of purified water (20 kg) to obtain a uniform solution.
  • This solution and (2R) -2-propyloctanoic acid (0.9 kg) were put into a soft capsule filling machine (rotary soft capsule molding machine H-1 type; force mata) and (2R) 2-propyloctanoic acid was filled.
  • a soft capsule live ball was obtained.
  • the obtained live spheres were sequentially subjected to tumbler drying and shelf drying to obtain soft capsules (2200 capsules) containing 300 mg of (2R) 2-propyloctanoic acid in one capsule.
  • (2R) -2 prophylaxis or treatment of functional brain disease comprising 2-propyloctanoic acid or a salt thereof and Z or suppression of symptom progression disclosed in the present invention includes, for example, depression, menopause It can be safely administered to patients with functional brain diseases such as mood disorders, perimenopausal mood disorders, panic disorder, irritable bowel syndrome, social anxiety disorder, post-traumatic stress disorder, etc. It is very useful as a medicine because of its prevention, treatment and Z or symptom progression-suppressing effects.
  • the “prevention, treatment and Z or symptom progression inhibition of functional brain diseases comprising (2R) -2-propyloctanoic acid or a salt thereof” disclosed in the present invention is conventionally used. Since it can be used in combination with existing drugs, it can also be administered to patients who are already using existing drugs.

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Abstract

La présente invention concerne un agent de prévention, de traitement et/ou d'inhibition de progression d'une maladie fonctionnelle du cerveau. La présente invention concerne spécifiquement un agent de prévention, de traitement et/ou d'inhibition de progression d'une maladie fonctionnelle du cerveau, ledit agent comprenant de l'acide (2R)-2-propyloctanoïque ou un sel dudit acide. L'agent peut être administré sans danger à un patient souffrant d'une maladie fonctionnelle du cerveau telle que dépression, trouble de l'humeur ménopausique, trouble de l'humeur périménopausique, trouble panique, syndrome du côlon irritable, trouble d'anxiété sociale et trouble de stress post-traumatique, et présente d'excellents effets.
PCT/JP2007/054512 2006-03-09 2007-03-08 Agent thérapeutique contre une maladie fonctionnelle du cerveau WO2007102571A1 (fr)

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US12/282,298 US9517221B2 (en) 2006-03-09 2007-03-08 (2R)-2-propyloctanoic acid for functional brain disease
ES07738003T ES2384034T3 (es) 2006-03-09 2007-03-08 Agente terapéutico para una enfermedad cerebral funcional
EP07738003A EP1997486B1 (fr) 2006-03-09 2007-03-08 Agent thérapeutique contre une maladie fonctionnelle du cerveau
JP2008503903A JP5195418B2 (ja) 2006-03-09 2007-03-08 機能性脳疾患治療剤
US15/342,046 US20170049737A1 (en) 2006-03-09 2016-11-02 (2r)-2-propyloctanoic acid for functional brain disease

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Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0048982A1 (fr) 1980-09-30 1982-04-07 Hans Weitzel Elément pour la toiture en matière plastique pour l'aquisition d'énergie solaire
JPH0332447B2 (fr) 1982-12-28 1991-05-13 Aoki Shigeto
EP0632008A1 (fr) 1993-06-01 1995-01-04 Ono Pharmaceutical Co., Ltd. Dérivés de l'acide pentanoique
JP3084345B2 (ja) 1995-04-26 2000-09-04 小野薬品工業株式会社 光学活性な２−プロピルオクタン酸の製造方法
EP1174131A1 (fr) 2000-07-18 2002-01-23 Ono Pharmaceutical Co., Ltd. Medicament pour le traitement de la maladie de Parkinson contenant un agent améliorant la fonction des astrocytes
JP2002097158A (ja) * 2000-07-18 2002-04-02 Ono Pharmaceut Co Ltd アストロサイト機能改善剤を有効成分として含有するパーキンソン病治療剤
JP2003051852A (ja) 2001-08-08 2003-02-21 Isola Communications:Kk メールメディアの記事情報の配信システム及び配信方法
JP2003097851A (ja) 2001-09-25 2003-04-03 Matsushita Electric Works Ltd 温水装置
JP2004092113A (ja) 2002-08-30 2004-03-25 Matsushita Electric Ind Co Ltd 人体乾燥装置
JP2004110972A (ja) 2002-09-19 2004-04-08 Ricoh Co Ltd チルト補正方法、チルト補正プログラム及び光ディスク装置
WO2005032535A1 (fr) 2003-10-03 2005-04-14 Ono Pharmaceutical Co., Ltd. Promoteurs de regeneration nerveuse
JP2005105722A (ja) 2003-10-01 2005-04-21 Eidai Co Ltd 壁構成部材
JP2005247841A (ja) * 2004-02-04 2005-09-15 Fancl Corp 抗不安剤
AR068397A1 (es) 2008-09-10 2009-11-11 Ingersoll Argentina S A Disco tapador de surcos
AR089855A1 (es) 2012-02-01 2014-09-24 Hochland Se Procedimiento para separar y apilar rajas de alimentos

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2006016319A (ja) * 2004-06-30 2006-01-19 Ono Pharmaceut Co Ltd プロドラッグ
AU2006287378A1 (en) * 2005-09-07 2007-03-15 Braincells, Inc. Modulation of neurogenesis by HDac inhibition
WO2007130419A2 (fr) * 2006-05-04 2007-11-15 Merck & Co., Inc. Inhibiteurs de l'histone desacétylase pour le traitement de la neurodégénération

Patent Citations (15)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0048982A1 (fr) 1980-09-30 1982-04-07 Hans Weitzel Elément pour la toiture en matière plastique pour l'aquisition d'énergie solaire
JPH0332447B2 (fr) 1982-12-28 1991-05-13 Aoki Shigeto
EP0632008A1 (fr) 1993-06-01 1995-01-04 Ono Pharmaceutical Co., Ltd. Dérivés de l'acide pentanoique
JP3084345B2 (ja) 1995-04-26 2000-09-04 小野薬品工業株式会社 光学活性な２−プロピルオクタン酸の製造方法
EP1174131A1 (fr) 2000-07-18 2002-01-23 Ono Pharmaceutical Co., Ltd. Medicament pour le traitement de la maladie de Parkinson contenant un agent améliorant la fonction des astrocytes
JP2002097158A (ja) * 2000-07-18 2002-04-02 Ono Pharmaceut Co Ltd アストロサイト機能改善剤を有効成分として含有するパーキンソン病治療剤
JP2003051852A (ja) 2001-08-08 2003-02-21 Isola Communications:Kk メールメディアの記事情報の配信システム及び配信方法
JP2003097851A (ja) 2001-09-25 2003-04-03 Matsushita Electric Works Ltd 温水装置
JP2004092113A (ja) 2002-08-30 2004-03-25 Matsushita Electric Ind Co Ltd 人体乾燥装置
JP2004110972A (ja) 2002-09-19 2004-04-08 Ricoh Co Ltd チルト補正方法、チルト補正プログラム及び光ディスク装置
JP2005105722A (ja) 2003-10-01 2005-04-21 Eidai Co Ltd 壁構成部材
WO2005032535A1 (fr) 2003-10-03 2005-04-14 Ono Pharmaceutical Co., Ltd. Promoteurs de regeneration nerveuse
JP2005247841A (ja) * 2004-02-04 2005-09-15 Fancl Corp 抗不安剤
AR068397A1 (es) 2008-09-10 2009-11-11 Ingersoll Argentina S A Disco tapador de surcos
AR089855A1 (es) 2012-02-01 2014-09-24 Hochland Se Procedimiento para separar y apilar rajas de alimentos

Non-Patent Citations (6)

* Cited by examiner, † Cited by third party
Title
"Comprehensive Organic Transformations: A Guide to Functional Group Preparations", 1999, JOHN WILEY & SONS INC.
"lyakuhin Tenkabutsu Jiten", 2000, THE JAPANESE SOCIETY OF PHARMACEUTICAL ADDITIVES
B. BONAZ, BRAIN RES., vol. 641, 1994, pages 21 - 28
MANEV R. ET AL.: "Could treatment with arundic acid (ONO-2506) increase vulnerability for depression?", MED. HYPOTHESES, vol. 67, no. 5, 2006, pages 1170 - 1172, XP005627426 *
See also references of EP1997486A4 *
SHINAGAWA R.: "Nokosoku Kyuseiki ni Okeru Astrocyte Tokuiteki Tanpaku S100 no Yakuwari", FOLIA PHARMACOLOGICA JAPONICA, vol. 127, no. 6, 2006, pages 485 - 488, XP003017611 *

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EP1997486B1 (fr) 2012-05-16
JPWO2007102571A1 (ja) 2009-07-23
US20090036529A1 (en) 2009-02-05
JP5195418B2 (ja) 2013-05-08
EP1997486A4 (fr) 2010-03-24
ES2384034T3 (es) 2012-06-28
US9517221B2 (en) 2016-12-13
EP1997486A1 (fr) 2008-12-03

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